Project Summary/Abstract Everyday life consists of a continuous stream of information. Yet, like chapter in a book, we tend to remember past experiences as more discrete and discontinuous, broken down into individual memories, or episodes. But what is an ?episode? in episodic memory? How do we associate time with specific events? Evidence suggests that linking sequential items in memory is supported by shared contextual features, such as items appearing in the same space. By contrast, when contextual inputs suddenly change, a theoretical ?event boundary? promotes separation in memory by defining a meaningful transition from one event to the next. Although this ebb and flow between memory integration and separation processes is essential to healthy cognition, surprisingly little is known about the mechanisms that support these fundamental features of episodic memory. One possibility is that neuromodulatory signals biases these dynamic processes towards memory separation, given that salient occurrences activate brainstem arousal systems known to reorient attention and encode new memories. The goal of this proposal is to test the role of sympathetic arousal in mediating the effects of event boundaries on episodic memory organization. In particular, we will test if arousal system activity, particularly in the locus coeruleus-norepinephrine (LC-NE) system, at event boundaries modulates memory representations in the hippocampus, leading to changes in how we integrate and recall prior sequences of information. Research in animals indicates that LC activity regulates sensory and mnemonic processes in the hippocampus, which helps represent context and link memories together in time. LC projections are particularly dense to the hippocampal CA3/dentate gyrus subregions, known to play a role in memory formation by recruiting different subsets of neurons to distinguish one context from another. We propose that increases in arousal and possibly LC activity at event boundaries serves to reconfigure hippocampal memory representations; in turn, such modulation of hippocampal activity and functional connectivity leads to changes in how we recall the order and timing of recent experiences. To test these predictions, we will combine high- resolution functional magnetic resonance imaging (fMRI) of the medial temporal lobe/brainstem with measures of pupil dilation, a biomarker of arousal, to measure human brain activity during sequence learning. Specific Aim 1 will examine how pupil dilation relates to different temporal memory outcomes at event boundaries, including memory for item order and subjective estimates of temporal distance between items. Specific Aim 2 will examine whether arousal and LC activity at event boundaries modulate trial-level and temporally dynamic patterns of activity in hippocampal subfields across time. Specific Aim 3 will formalize these predictions by leveraging an influential computational model of temporal context to predict how arousal at boundaries influences temporal memory. In line with the goals of NIMH, elucidating this core memory circuitry will offer new insight into targeted interventions that can improve memory and wellbeing.